The present invention relates to potent substituted N-arylsulfonylated-proline derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesion-mediated pathologies. This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
Many physiological processes require that cells come into close contact with other cells and/or extracellular matrix. Such adhesion events may be required for cell activation, migration, proliferation and differentiation. Cell-cell and cell-matrix interactions are mediated through several families of cell adhesion molecules (CAMs) including the selectins, integrins, cadherins and immunoglobulins. CAMs play an essential role in both normal and pathophysiological processes. Therefore, the targeting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell-cell and cell-matrix interactions.
The integrin superfamily is made up of structurally and functionally related glycoproteins consisting of a and b heterodimeric, transmembrane receptor molecules found in various combinations on nearly every mammalian cell type. VLA-4 (“very late antigen-4”; CD49d/CD29; or α4β1) is an integrin expressed on all leukocytes, except platelets and mature neutrophils, including dendritic cells and macrophage-like cells and is a key mediator of the cell-cell and cell-matrix interactions of these cell types. The ligands for VLA-4 include vascular cell adhesion molecule-1 (VCAM-1) and the CS-1 domain of fibronectin (FN). VCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells at sites of inflammation. VCAM-1 is produced by vascular endothelial cells in response to proinflammatory cytokines The CS-1 domain is a 25 amino acid sequence that arises by alternative splicing within a region of fibronectin. A role for VLA-4/CS-1 interactions in inflammatory conditions has been proposed (see M. J. Elices, “The integrin α4β1 (VLA-4) as a therapeutic target” in Cell Adhesion and Human Disease, Ciba Found. Symp., John Wiley & Sons, NY, 1995, p. 79).
α4β7 (also referred to as LPAM-1 and α4βp) is an integrin expressed on leukocytes and is a key mediator of leukocyte trafficking and homing in the gastrointestinal tract. The ligands for α4β7 include mucosal addressing cell adhesion molecule-1 (MadCAM-1) and, upon activation of α4β7, VCAM-1 and fibronectin (Fn). MadCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells of gut-associated mucosal tissues of the small and large intestine (“Peyer's Patches”) and lactating mammary glands. MadCAM-1 can be induced in vitro by proinflammatory stimuli. MadCAM-1 is selectively expressed at sites of lymphocyte extravasation and specifically binds to the integrin, α4β7.
The α9β1 integrin is found on airway smooth muscle cells, non-intestinal epithelial cells, and neutrophils, and, less so, on hepatocytes and basal keratinocytes. Neutrophils, in particular, are intimately involved in acute inflammatory responses. Attenuation of neutrophil involvement and/or activation would have the effect of lessening the inflammation. Thus, inhibition of α9β1 binding to its respective ligands would be expected to have a positive effect in the treatment of acute inflammatory conditions.
Neutralizing anti-α4 antibodies or blocking peptides that inhibit the interaction between VLA-4 and/or α4β7 and their ligands have been shown efficacious both prophylactically and therapeutically in several animal models of disease, including i) experimental allergic encephalomyelitis, a model of neuronal demyelination resembling multiple sclerosis; ii) bronchial hyperresponsiveness in sheep and guinea pigs as models for the various phases of asthma; iii) adjuvant-induced arthritis in rats as a model of inflammatory arthritis; iv) adoptive autoimmune diabetes in the NOD mouse; v) cardiac allograft survival in mice as a model of organ transplantation; vi) spontaneous chronic colitis in cotton-top tamarins which resembles human ulcerative colitis, a form of inflammatory bowel disease; vii) contact hypersensitivity models as a model for skin allergic reactions; viii) acute nephrotoxic nephritis; ix) tumor metastasis; x) experimental autoimmune thyroiditis; xi) ischemic tissue damage following arterial occlusion in rats; and xii) inhibition of TH2 T-cell cytokine production including IL-4 and IL-5 by VLA-4 antibodies which would attenuate allergic responses (J. Clinical Investigation 100, 3083 (1997). The primary mechanism of action of such antibodies appears to be the inhibition of lymphocyte and monocyte interactions with CAMs associated with components of the extracellular matrix, thereby limiting leukocyte migration to extravascular sites of injury or inflammation and/or limiting the priming and/or activation of leukocytes. Animal models of these diseases may also be used to demonstrate efficacy of small molecule VLA-4 antagonists
There is additional evidence supporting a possible role for VLA-4 interactions in other diseases, including rheumatoid arthritis; various melanomas, carcinomas, and sarcomas, including multiple myeloma; inflammatory lung disorders; acute respiratory distress syndrome (ARDS); pulmonary fibrosis; atherosclerotic plaque formation; restenosis; uveitis; and circulatory shock (for examples, see A. A. Postigo et al., “The α4β1/VCAM-1 adhesion pathway in physiology and disease.”, Res. Immunol., 144, 723 (1994) and J.-X. Gao and A. C. Issekutz, “Expression of VCAM-1 and VLA-4 dependent T-lymphocyte adhesion to dermal fibroblasts stimulated with proinflammatory cytokines.” Immunol. 89, 375 (1996)).
At present, there is a humanized monoclonal antibody (Antegren®, Athena Neurosciences/Elan) against VLA-4 in clinical development for the treatment of multiple sclerosis and Crohn's disease and a humanized monoclonal antibody (ACT-1®/LDP-02 LeukoSite) against α4β7 in clinical development for the treatment of inflammatory bowel disease. There are also several VLA-4 antagonists in early clinical trials for treatment of asthma and arthritis. There still remains a need for potent low molecular weight inhibitors of VLA-4-, α4β7- and/or α9β1 dependent cell adhesion that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.
PCT Application No. WO98/53818 discloses compounds having activity as inhibitors of binding between VCAM-1 and cells expressing VLA-4, and having the formula: 
PCT Application No. WO98/53814 discloses compounds having activity as inhibitors of binding between VCAM-1 and cells expressing VLA-4, and having the formula: 
PCT Application No. WO98/53814 discloses compounds having activity as inhibitors of binding between VCAM-1 and cells expressing VLA-4, and having the formula: 
PCT Application Nos. WO99/06390, WO99/06431, WO99/06432, WO99/06433, WO99/06434, WO99/06435, WO99/06436, and WO99/06437 disclose compounds having activity as inhibitors of binding between VCAM-1 and cells expressing VLA-4, and having the formula: 